Diosgenin derivative and preparation method and application thereof
阅读说明：本技术 一种薯蓣皂苷元衍生物及其制备方法和应用 (Diosgenin derivative and preparation method and application thereof ) 是由 刘玉法 王目旋 彭立增 王继庆 井晓琳 王磊 于 2019-10-12 设计创作，主要内容包括：本发明提供了一种薯蓣皂苷元衍生物及其制备方法和应用,该薯蓣皂苷元衍生物具有式(I)所示结构：<Image he="314" wi="700" file="DDA0002231534840000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R为被取代基取代的苯基,所述取代基选自烷基、烷氧基和卤素；以及,本发明还提供了(I)化合物的药学上可接受的盐。本发明的化合物对胆管癌细胞和人胰腺癌细胞增殖具有较好的抑制活性,本发明化合物对胆管癌细胞和人胰腺癌细胞增殖的具有很好的抑制活性,显著优于临床应用的5-氟尿嘧啶。(The invention provides a diosgenin derivative, a preparation method and an application thereof, wherein the diosgenin derivative has a structure shown in a formula (I): wherein R is phenyl substituted with a substituent selected from the group consisting of alkyl, alkoxy, and halogen; also, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I). The compound has good inhibitory activity on proliferation of bile duct cancer cells and human pancreatic cancer cells, and is obviously superior to clinical 5-fluorouracil.)
1. A diosgenin derivative having the structure represented by formula (I):
wherein R is phenyl substituted with a substituent selected from the group consisting of alkyl, alkoxy, and halogen;
or a pharmaceutically acceptable salt of the compound of formula (I).
2. The diosgenin derivative according to claim 1, wherein R is selected from the group consisting of:
wherein R is1Substituted on the benzene ring, mono-or polysubstituted, R1Selected from halogens; r2Is C1-5An alkyl group; the polysubstitution is disubstituted, trisubstituted, tetrasubstituted or pentasubstituted;
preferably, R1One or more selected from the group consisting of F, Cl, Br and I; r2Is C1-3An alkyl group.
3. A diosgenin derivative according to claim 1 or 2, wherein R is
preferably, R is selected from
4. A diosgenin derivative according to claim 1 or 2, wherein R is selected from the following groups: o-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl group, (3, 4-difluoro) phenyl group, (2, 3-difluoro) phenyl group, (2, 4-difluoro) phenyl group, (2, 5-difluoro) phenyl group, (2, 6-difluoro) phenyl group, (3, 5-difluoro) phenyl group, (2,4, 6-trifluoro) phenyl group, (3,4, 5-trifluoro) phenyl group, pentafluorophenyl group, 2-methoxy-3-chlorophenyl group, 2-methoxy-4-chlorophenyl group, 2-methoxy-5-chlorophenyl group, 2-methoxy-6-chlorophenyl group, 2-methoxy-3-fluorophenyl group, 2-methoxy-4-fluorophenyl group, 2-methoxy-5-fluorophenyl group, 2-methoxy-6-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl group, 3, 4-difluoro) phenyl group, 2, 3-difluoro) phenyl group, 2, 2-methoxy-3-bromophenyl, 2-methoxy-4-bromophenyl, 2-methoxy-5-bromophenyl, 2-methoxy-3-iodophenyl, 2-methoxy-4-iodophenyl, 2-methoxy-5-iodophenyl, 4-methoxy-2-chlorophenyl, 4-methoxy-3-chlorophenyl, 4-methoxy-2-fluorophenyl, 4-methoxy-3-fluorophenyl, 4-methoxy-2-bromophenyl, 4-methoxy-3-bromophenyl, 4-methoxy-2-iodophenyl, 4-methoxy-3-iodophenyl, 2-methyl-3-chlorophenyl, methyl-3-pyridyl, methyl-2, 2-methyl-4-chlorophenyl group, 2-methyl-5-chlorophenyl group, 2-methyl-6-chlorophenyl group, 2-methyl-3-fluorophenyl group, 2-methyl-4-fluorophenyl group, 2-methyl-5-fluorophenyl group, 2-methyl-6-fluorophenyl group, 2-methyl-3-bromophenyl group, 2-methyl-4-bromophenyl group, 2-methyl-5-bromophenyl group, 2-methyl-6-bromophenyl group, 2-methyl-3-iodophenyl group, 2-methyl-4-iodophenyl group, 2-methyl-5-iodophenyl group, 3-methyl-2-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2-methyl-6-fluorophenyl group, 2-methyl-3-iodophenyl group, 2-methyl-5-iodo, 3-methyl-5-chlorophenyl group, 3-methyl-4-fluorophenyl group, 3-methyl-5-fluorophenyl group, 3-methyl-4-bromophenyl group, 3-methyl-5-bromophenyl group, 3-methyl-4-iodophenyl group, 3-methyl-5-iodophenyl group, 4-methyl-2-chlorophenyl group, 4-methyl-3-chlorophenyl group, 4-methyl-2-fluorophenyl group, 4-methyl-3-fluorophenyl group, 4-methyl-2-bromophenyl group, 4-methyl-3-bromophenyl group, 4-methyl-2-iodophenyl group, 4-methyl-3-iodophenyl group, 4-chloro-3-methoxyphenyl group, 3-fluorophenyl group, 3-methyl-4-fluorophenyl group, 3-iodophenyl group, 3-methyl-2-iodophenyl group, 3-methyl-3-, 4-bromo-3-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 4-iodo-3-methoxyphenyl, 2-chloro-3-methoxyphenyl, 2-bromo-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 2-iodo-3-methoxyphenyl, 5-chloro-3-methoxyphenyl, 5-bromo-3-methoxyphenyl, 5-fluoro-3-methoxyphenyl, 5-iodo-3-methoxyphenyl, 5-chloro-3-ethoxyphenyl, 5-bromo-3-ethoxyphenyl, 5-fluoro-3-ethoxyphenyl and 5-iodo-3-ethoxyphenyl.
5. The preparation method of the diosgenin derivative shown in the formula (I) is characterized by comprising the steps of taking diosgenin as an initial reactant and reacting with RCH (Richardson fatty acid)2X reacts to obtain a compound shown in a formula (I);
wherein R is as defined in any one of claims 1 to 4 and X is halogen.
6. A process according to claim 5, which comprises dissolving diosgenin in a solvent and adding RCH2X reacts with alkaline substances, and the solution is kept alkaline in the reaction process to prepare the compound shown in the formula (I);
preferably, the reaction temperature is-20-300 ℃, and the reaction time is 0.1-72 h;
the solvent is selected from one or more of water, methanol, ethanol, propanol, butanol, pentanol, glycerol, dichloromethane, trichloromethane, carbon tetrachloride, benzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, tetrahydrofuran, N-dimethylformamide, ethyl acetate and dimethyl sulfoxide; preferably any one of n-propanol, isopropanol, n-butanol, ethyl acetate, butyl acetate, absolute ethanol, methanol, dichloromethane and tetrahydrofuran;
preferably, the amount of the solvent is such that each mole of diosgenin is dissolved in 5-100L of solvent;
preferably, the alkaline substance is selected from gamma-Al2O3-Na、γ-Al2O3-K、γ-Al2O3-NaOH-Na、γ-Al2O3-NaOH-K、γ-Al2O3-KOH-Na、γ-Al2O3-one or more of KOH-K, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium amide, sodium metal, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium oxide, potassium oxide, calcium oxide, strontium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, ammonia, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, pyridine, and piperidine; preferably trimethylamine, triethylamine and gamma-Al2O3-NaOH-K、γ-Al2O3-KOH-Na, sodium hydride, potassium hydride, sodium ethoxide, strontium carbonate, potassium carbonate, diethylamine, triethylamine or sodium tert-butoxide;
preferably, the diosgenin and RCH are2X and the molar ratio of the alkaline substances is 1: (0.05-15): (0.01-15).
7. The method as claimed in claim 5 or 6, further comprising detecting the end point of the reaction by chromatography, standing the reaction product at room temperature after the reaction is finished, and preparing the compound of formula (I) by separation and purification;
preferably, the separation and purification method is selected from one or more of filtration, resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment and chromatography.
8. A composition comprising a diosgenin derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical formulation comprising a diosgenin derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a composition according to claim 8, together with at least one pharmaceutical carrier or adjuvant.
10. Use of a diosgenin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or a composition according to claim 8, or a pharmaceutical formulation according to claim 9, in the manufacture of an anti-cancer medicament;
preferably, the cancer is selected from pancreatic cancer and cholangiocarcinoma.
Technical Field
The invention relates to the field of biological medicines, in particular to a diosgenin derivative and a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Pancreatic cancer is a common pancreatic tumor, is a digestive tract malignant tumor with high malignancy degree and difficult diagnosis and treatment, and has 5-year survival rate of less than 1 percent. The early diagnosis rate of pancreatic cancer is low, the operative mortality rate is high, and the early diagnosis rate is one of the worst malignant tumors. At present, the main therapeutic drugs comprise fluorouracil, doxorubicin, ifosfamide, semustine, paclitaxel, gemcitabine, cisplatin and the like, but the clinical cure rate is very low, so that research and development of anti-pancreatic cancer drugs with better curative effect are very necessary.
Cholangiocarcinoma is a common biliary tract malignant tumor, with high malignancy, very poor prognosis, and increasing morbidity and mortality year by year (wangxian, et al, the clinical treatment progress of hepatoportal cholangiocarcinoma [ J ], electronic journal of Chinese liver surgery, 2018, 7(4): 253-containing 257). The common chemotherapy drugs in the clinic of bile duct cancer are 5-fluorouracil and cisplatin. When the 5-fluorouracil reaches 20ug/mL, the traditional Chinese medicine composition has a good effect of inhibiting the growth of human bile duct cancer QBC939 cells, and has side effects of bone marrow inhibition such as leukopenia and platelet drop, and gastrointestinal reactions such as inappetence, nausea, vomiting, stomatitis, gastritis, abdominal pain and diarrhea. When the cisplatin reaches 3.0 mu g/mL, the cisplatin has a good effect of inhibiting cell growth of human bile duct cancer QBC939, and mainly has severe digestive tract reactions such as nausea and vomiting, renal toxicity such as renal tubular injury, and more common neurotoxicity such as tinnitus and hearing loss caused by auditory nerve damage. Because biliary duct cancer has hidden onset and difficult early diagnosis and has late clinical symptoms, epidemiological studies show that only 10-15% of patients are likely to be cured by operation, and many patients find that the patients are in late stage, but the postoperative recurrence rate is still 50-60%, and the five-year survival rate is only 30%. At present, the treatment principle of the bile duct cancer still adopts a comprehensive treatment scheme mainly based on surgical resection, but only patients with deficiency of 1/3 can be surgically resected when the diagnosis is confirmed, the surgical prognosis is poor, and the combined chemotherapy has no ideal effect on locally advanced or metastatic unresectable bile duct cancer. Therefore, the development of new therapeutic drugs is urgently required.
Diosgenin (CAS number: 512-06-1) is a steroid compound obtained by hydrolyzing and deglycosylating dioscin contained in rhizome of Dioscoreaceae plants such as Dioscorea zingiberensis, Dioscorea nipponica, Dioscorea panthaica and the like, and is an important raw material for synthesizing steroid hormone drugs and steroid contraceptives. Dioscin has certain anticancer activity (application of protodioscin in preparation of drug-resistant osteosarcoma medicine CN201810091212.3), has activity on lung cancer cells A549(Wei Y, et al. Anti-cancer effects of Dioscin on third genes of human lung cancer cells line identification DNA damage and activating mitotic cancer therapy, 2013, 59), stomach cancer cells MGC-803 (Zhuao X, et al. patent effects of diosgenin targeting cancer in vitro and vivo. phytochrome therapy, 2016, 23), liver cancer cells Hu 7(Hsieh M J, et al. autoinjection therapy, apoptosis induced breast cancer cells 7. basic, and cancer cells ROS, and has activity on lung cancer cells A549 (cancer cells ROS, tissue culture cell ROS, see 3, 2016. 3, 23), liver cancer cells Hu-7 (tumor diagnosis cells, mouse tissue culture medium J, et al. apoptosis inducing hormone, cancer cells, calcium cancer, diosgenin also has certain activity on sarcoma-180, hepatoma ascites type, mouse cervical cancer, and ehrlich ascites carcinoma (new pharmaceutical use of diosgenin CN 01129317.9).
Disclosure of Invention
The present invention is directed to overcoming the above-mentioned disadvantages and providing a diosgenin derivative, a method for preparing the same, and use thereof. The diosgenin derivative has good inhibitory activity on proliferation of bile duct cancer cells and human pancreatic cancer cells, the inhibitory rate of the diosgenin derivative on proliferation of bile duct cancer cells and human pancreatic cancer cells is generally higher than 80% at 0.2ug/mL, and the activity of the diosgenin derivative is far higher than that of 5-fluorouracil for clinical application.
Specifically, the invention has the following technical scheme:
in a first aspect of the invention, the invention provides a compound having the structure shown in formula (I):
wherein R is phenyl substituted with a substituent selected from the group consisting of alkyl, alkoxy, and halogen;
also, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I).
Examples of the "pharmaceutically acceptable salt" may include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; organic acid salts such as acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and ascorbate; inorganic base salts such as sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt and aluminum salt; and organic base salts such as arginine salt, benzathine salt, choline salt, diethylamine salt, dialcohol amine salt, glycinate salt, lysine salt, meglumine salt, ethanolamine salt, and tromethamine salt.
In an embodiment of the invention, R is selected from the following groups:
wherein, in the above optional groups, R1Represents a single or multiple substitution at any position of a benzene ring, R1Selected from halogens; r2Is C1-5Alkyl groups of (a); the polysubstitution is disubstituted, trisubstituted, tetrasubstituted or pentasubstituted.
In an embodiment of the invention, R1One or more selected from the group consisting of F, Cl, Br and I, which may be the same or different; r2Is C1-3An alkyl group.
In an embodiment of the invention, R is
In an embodiment of the invention, R is selected from
In an embodiment of the invention, said R is selected from the following groups: o-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl group, (3, 4-difluoro) phenyl group, (2, 3-difluoro) phenyl group, (2, 4-difluoro) phenyl group, (2, 5-difluoro) phenyl group, (2, 6-difluoro) phenyl group, (3, 5-difluoro) phenyl group, (2,4, 6-trifluoro) phenyl group, (3,4, 5-trifluoro) phenyl group, pentafluorophenyl group, 2-methoxy-3-chlorophenyl group, 2-methoxy-4-chlorophenyl group, 2-methoxy-5-chlorophenyl group, 2-methoxy-6-chlorophenyl group, 2-methoxy-3-fluorophenyl group, 2-methoxy-4-fluorophenyl group, 2-methoxy-5-fluorophenyl group, 2-methoxy-6-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl group, 3, 4-difluoro) phenyl group, 2, 3-difluoro) phenyl group, 2, 2-methoxy-3-bromophenyl, 2-methoxy-4-bromophenyl, 2-methoxy-5-bromophenyl, 2-methoxy-3-iodophenyl, 2-methoxy-4-iodophenyl, 2-methoxy-5-iodophenyl, 4-methoxy-2-chlorophenyl, 4-methoxy-3-chlorophenyl, 4-methoxy-2-fluorophenyl, 4-methoxy-3-fluorophenyl, 4-methoxy-2-bromophenyl, 4-methoxy-3-bromophenyl, 4-methoxy-2-iodophenyl, 4-methoxy-3-iodophenyl, 2-methyl-3-chlorophenyl, methyl-3-pyridyl, methyl-2, 2-methyl-4-chlorophenyl group, 2-methyl-5-chlorophenyl group, 2-methyl-6-chlorophenyl group, 2-methyl-3-fluorophenyl group, 2-methyl-4-fluorophenyl group, 2-methyl-5-fluorophenyl group, 2-methyl-6-fluorophenyl group, 2-methyl-3-bromophenyl group, 2-methyl-4-bromophenyl group, 2-methyl-5-bromophenyl group, 2-methyl-6-bromophenyl group, 2-methyl-3-iodophenyl group, 2-methyl-4-iodophenyl group, 2-methyl-5-iodophenyl group, 3-methyl-2-chlorophenyl group, 3-methyl-4-chlorophenyl group, 2-methyl-6-fluorophenyl group, 2-methyl-3-iodophenyl group, 2-methyl-5-iodo, 3-methyl-5-chlorophenyl group, 3-methyl-4-fluorophenyl group, 3-methyl-5-fluorophenyl group, 3-methyl-4-bromophenyl group, 3-methyl-5-bromophenyl group, 3-methyl-4-iodophenyl group, 3-methyl-5-iodophenyl group, 4-methyl-2-chlorophenyl group, 4-methyl-3-chlorophenyl group, 4-methyl-2-fluorophenyl group, 4-methyl-3-fluorophenyl group, 4-methyl-2-bromophenyl group, 4-methyl-3-bromophenyl group, 4-methyl-2-iodophenyl group, 4-methyl-3-iodophenyl group, 4-chloro-3-methoxyphenyl group, 3-fluorophenyl group, 3-methyl-4-fluorophenyl group, 3-iodophenyl group, 3-methyl-2-iodophenyl group, 3-methyl-3-, 4-bromo-3-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 4-iodo-3-methoxyphenyl, 2-chloro-3-methoxyphenyl, 2-bromo-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 2-iodo-3-methoxyphenyl, 5-chloro-3-methoxyphenyl, 5-bromo-3-methoxyphenyl, 5-fluoro-3-methoxyphenyl, 5-iodo-3-methoxyphenyl, 5-chloro-3-ethoxyphenyl, 5-bromo-3-ethoxyphenyl, 5-fluoro-3-ethoxyphenyl and 5-iodo-3-ethoxyphenyl.
Further, in some embodiments of the invention, the compounds of formula (I) of the present invention include the compounds shown in table 1:
TABLE 1 Structure of the compound of formula (I) and HR-MS structural analysis thereof
In a second aspect of the invention, there is also provided a process for the preparation of a compound of formula (I), which process comprises reacting diosgenin as an initial reactant with RCH2X reacts to obtain a compound shown in a formula (I); wherein R is as defined above for the first aspect of the invention and X is a halogen selected from F, Cl, Br and I, preferably Cl or Br.
In an embodiment of the invention, the method comprises dissolving diosgenin in a solvent, adding RCH2And reacting X with a basic substance, and keeping the solution to be basic (pH 7-14) in the reaction process to prepare the compound shown in the formula (I).
In the embodiment of the invention, the reaction temperature is-20-300 ℃, and the reaction time is 0.1-72 h; preferably, the reaction temperature is-20 to 150 ℃, more preferably-10 to 120 ℃, at which the reaction proceeds more easily.
In an embodiment of the present invention, the solvent is selected from one or more of water, methanol, ethanol (anhydrous ethanol is preferred), propanol, butanol, pentanol, glycerol, dichloromethane, trichloromethane, carbon tetrachloride, benzene, toluene, di-10 toluene, 1, 4-dioxane, 1, 2-dichloroethane, tetrahydrofuran, N-Dimethylformamide (DMF), and ethyl acetate and dimethyl sulfoxide (DMSO); any one of n-propanol, isopropanol, n-butanol, ethyl acetate, butyl acetate, absolute ethanol, methanol, dichloromethane, and tetrahydrofuran is preferable, and among these solvents, the reaction proceeds more easily.
In an embodiment of the present invention, the solvent is used in an amount of 5-100L per mole of diosgenin dissolved in the solvent.
In an embodiment of the invention, the alkaline substance is selected from γ -Al2O3-Na、γ-Al2O3-K、γ-Al2O3-NaOH-Na、γ-Al2O3-NaOH-K、γ-Al2O3-KOH-Na、γ-Al2O3-KOH-K, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium amide, sodium metal, sodium hydride, sodium hydroxide, potassium hydroxide, hydrogen hydroxideOne or more of calcium oxide, sodium oxide, potassium oxide, calcium oxide, strontium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, ammonia, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, pyridine and piperidine.
In some preferred embodiments, the basic substance is trimethylamine, triethylamine, γ -Al2O3-NaOH-K、γ-Al2O3KOH-Na, sodium hydride, potassium hydride, sodium ethoxide, strontium carbonate, potassium carbonate, diethylamine, triethylamine or sodium tert-butoxide, in the presence of these basic substances, the reaction proceeds more readily.
In an embodiment of the invention, the diosgenin, RCH2X and the molar ratio of the alkaline substances is 1: (0.05-15): (0.01-15), preferably 1: (0.1-10): (0.01-10), more preferably 1: (1.0-1.5): (0.6-1.5).
In an embodiment of the present invention, the preparation method of the compound of formula (I) according to the present invention further comprises detecting the end point of the reaction by chromatography, standing to room temperature after the reaction is finished, and separating and purifying to prepare the compound of formula (I).
In an embodiment of the present invention, the separation and purification method is selected from a combination of one or more of filtration, resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment, and chromatography.
The separation and purification method of the invention can be as follows: for example, in some further embodiments, the separation and purification method may be: detecting the total reaction of diosgenin by HPLC, reducing pressure to remove solvent, performing chromatography, such as chromatography with Agilent Zorbax SB-C18(4.6mm × 150mm,5um), eluting with acetonitrile-water (such as v/v ═ 90:10), performing HPLC tracing to separate and purify the reaction product, and drying the solid to obtain the target product. As another example, in some embodiments, the separation and purification process can be: detecting all reactions of diosgenin by HPLC, distilling off solvent until liquid volume is reduced to 1/4, cooling and crystallizing overnight, such as cooling to 5 deg.C and crystallizing overnight, filtering, tracking reaction and product separation and purification process by HPLC, and drying solid, such as drying at 60 deg.C for 4 hr, to obtain target product. And, for example, in some embodiments, TLC detects the total reaction of diosgenin, after warming to room temperature, water is added, dichloromethane, chloroform, acetone or ethyl acetate is used for extraction for 1 to more times, such as 3 times (such as 50-300mL × 3), TLC tracks the reaction and separation and purification process of the product, extract is recovered, and the obtained solid is dried, such as at 60 ℃, for 4 hours, to obtain the target product.
In a third aspect of the invention, the present invention also provides a composition comprising a compound of formula (I) as described in the above first aspect of the invention or a pharmaceutically acceptable salt thereof.
In a fourth aspect of the invention, the invention also provides a pharmaceutical formulation comprising a compound of formula (I) as described in the above first aspect of the invention or a pharmaceutically acceptable salt thereof or a composition comprising said compound of formula (I) or a salt thereof, together with at least one pharmaceutical carrier or adjuvant.
The compounds of the present invention or pharmaceutical compositions containing the compounds of the present invention may be in a variety of pharmaceutical dosage forms and administered in unit dosage form. The pharmaceutical or administration form may be a liquid form, a solid form, a topical formulation, a spray, and the like. The liquid dosage form can be true solution, colloid, microparticle, emulsion, or mixed suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, landfill, patch, liniment, etc.
The pharmaceutical composition or pharmaceutical preparation of the present invention may further comprise a conventional carrier, wherein the pharmaceutically acceptable carrier includes but is not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbates, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and the like. The carrier may be present in the pharmaceutical composition in an amount of 1% to 98% by weight, usually about 80% by weight.
Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may also be coated by methods known in the art of pharmacy.
The oral liquid can be made into suspension, solution, emulsion or syrup of water and oil, or made into dry product, and supplemented with water or other suitable medium before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, gum arabic; or a non-aqueous carrier (which may comprise an edible oil), such as almond oil, an oil such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoate, sorbic acid. Flavoring or coloring agents may be added if desired.
In a fifth aspect, the present invention also provides the use of a compound of formula (I) as described in the above first aspect of the present invention or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a salt thereof, or a pharmaceutical formulation comprising a compound of formula (I) or a salt thereof, in the manufacture of a medicament for the treatment of cancer; in an embodiment of the invention, the cancer is preferably pancreatic cancer and/or cholangiocarcinoma.
In some embodiments of the invention, the inhibition rate of 0.2ug/mL of the compound of formula (I) of the invention on the proliferation of bile duct cancer cells QBC-939 is higher than 80%, and can reach 95%; the inhibition rate of 0.2ug/mL of the compound shown in the formula (I) on the proliferation of human pancreatic cancer cells PANC-1 is higher than 80% and can reach 95%. The activity of the compound of the invention is far higher than that of 5-fluorouracil used clinically.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only, and one skilled in the art can prepare the compounds of the present invention by simple modification based on the teachings of the present invention.